PROJECT SUMMARY This application from the Chicagoland Metropolitan Asthma Consortium (CMAC) is in response to the RFA entitled ?Clinical Centers for the NHLBI's Precision Interventions for Severe and/or Exacerbation Prone Asthma (PrecISE) Network?. The Chicago metropolitan area has almost 10 million inhabitants who are racially and eth- nically diverse. The City of Chicago, which represents about one-third of this population, has an asthma preva- lence rates in both children and adults exceeding 10% and has one of the highest asthma mortality rates in the United States. Severe and/or exacerbation prone (S/EP) asthma affects over 10% of asthmatic patients and accounts for both substantial morbidity and a majority of asthma-related costs. While substantial progress has been made in helping patients control asthma symptoms, how to use current therapies to target specific phe- notypes precisely and prevent disease progression, and when and how to change these therapies in the event of failure, remain unclear. The CMAC includes academic medical center partners: Northwestern University, the University of Chicago, Lurie Children's Hospital, Rush University, and John H. Stroger Hospital, and an expan- sive network of Community Partners. The CMAC is uniquely qualified to participate in the PrecISE Network and contribute to the development and successful completion of the network clinical trials and proof of con- cept/mechanistic studies. Our key personnel have extensive experience in asthma clinical and translational research, including studies exploring its pathophysiology, pathogenesis (genetic and environmental factors), epidemiology and treatment; leadership roles in key research support and CTSA programs at their respective institutions; successful collaborations together and with multiple institutions and networks on asthma research programs; access to a large, diverse asthma population; and documented, successful ability to enroll patients in NIH, foundation and industry sponsored asthma research studies and clinical trials. We propose a model intervention sequential, adaptive clinical trial protocol with three targeted, precise interventions that will be guided by repeated assessment of biomarkers to inform both the initial therapy choice and subsequent inter- ventions. Further, our proposal utilizes the latest adaptive clinical trial design, careful longitudinal follow-up, and will use the responses of early-recruited patients to guide targeted therapy in subsequently-enrolled sub- jects. Our targeted interventions include three different anti-cytokine and prostaglandin therapies directed to Th2-high patients, and three different therapies directed to Th2-low, obese and lean patients. Participation by the CMAC will strengthen the PrecISE Network so that it will achieve its goal to complete successfully early- phase clinical trials to test targeted interventions in patients with S/EP asthma, generate new knowledge re- garding asthma phenotypes, predictive biomarkers and therapeutic responsiveness, and positively inform clini- cal practice in the treatment of patients with severe asthma.